In respiratory infectious diseases, multi-drug-resistant Pneumococcus is the most serious therapeutic target. Telithromycin, which is considered as the most effective drug against the Pneumococcus, induces a grave side effect; i.e., consciousness disorders. Therefore, development of an antibacterial agent which exhibits high antibacterial effect and induces reduced side effect is envisaged.
Under such circumstances, the present applicant previously found that quinolone compounds represented by formula (I):
(wherein n is an integer of 2 to 5; R1 represents a C1 to C4 alkyl group which may have a substituent, or an aryl group which may have a substituent; and R6 represents a hydrogen atom or a fluorine atom) can solve problems in the therapy of respiratory infectious diseases; for example, these compounds exhibit excellent bactericidal effect on multi-drug-resistant Pneumococcus as well as high safety and excellent in vivo behavior, and filed a patent application therefor (Patent Document 1). These compounds can be produced through condensation reaction between a spiroaminopyrrolidine compound having an asymmetric tetrasubstituted carbon atom represented by (6-1):
or such a spiroaminopyrrolidine compound in which the amino group attached to the ring is protected by a protective group and a boron-chelate of a quinolone-skeleton compound represented by, for example, the following formula:
or a carboxylic form of the quinolone-skeleton compound instead of the boron-chelated compound.
Among compounds represented by formula (6-1), a compound in which, for example, R1 is a methyl and n is 2 can be synthesized through the following steps: cyclization reaction between t-butyl acetoacetate (starting material) and alkylene dihalide; converting the formed cyclic compound to an amino-cyano compound by use of a cyanide compound (i.e., Strecker reaction); reducing the cyano group of the amino-cyano compound to convert to an aminomethyl group, thereby forming a diamino compound; performing ring-closure reaction through intramolecular lactamization between the amino group derived from the cyano group of the compound and a carboxylic moiety of the compound, to thereby form a spiroaminopyrrolidone compound having an asymmetric tetrasubstituted carbon atom; subsequently, protecting the amino group and the NH group of the pyrrolidone moiety of the compound; performing optical resolution of the racemic mixture through HPLC by use of an optically active column, to thereby form an optically active form; reducing pyrrolidone; and finally, removing the protective group attached to the ring nitrogen atom. The thus-proposed method isolates a single-isomer intermediate compound which can be employed in introduction of a substituent to the 7-position of a quinolone ring and which is used for producing a single-isomer compound represented by formula (I).

Meanwhile, there has been known a method for producing a spiro-ring-structure pyrrolidine compound having no alkyl group at the 3-position of its pyrrolidine ring (Patent Document 2).
Patent Document 1: JP 2005-146386
Patent Document 2: JP 09-208561